Utility of Protein Aggregation Assays from Laboratory to Clinical Application

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Background

Protein mis-folding disorders are a group of diseases that are associated with the deposition of a mis-folded form of a normally expressed constitutive protein to form characteristic inclusion bodies. These disorders are most commonly associated with progressive neurodegenerative diseases. The most characterized of these disorders are Creutzfeldt-Jakob disease (CJD) in which an abnormal form of prion protein (PrPSc) is deposited within the central nervous system (CNS). Other disorders include Parkinson's disease (PD), Lewy body dementia (LBD) and Multi-system atrophy (MSA) that are all associated with the deposition of abnormal forms of alpha-synuclein. In addition, Alzheimer's disease pathology includes misfolded beta-amyloid and tau protein. The prevalence of these disorders is increasing with the aging population, and this is of major public health concern.

Each of these pathologically misfolded proteins has the ability of inducing subsequent misfolding of normally folded proteins in a cyclical fashion. This self-seeding is a characteristic of these protein mis-folded disorders. The development of assays that can detect the presence of small amounts of these mis-folded proteins has been a major development in the investigation and understanding of these disorders. The most widely used assays are Protein Misfolding Cyclic Amplification (PMCA) and Real-Time Quaking Induced Conversion (RT-QuIC). Both of these assays imply that misfolded proteins (seeds) act as template for imparting their conformation to normal isoform (substrate) in a cyclical fashion and amplify the minute amounts of misfolded protein to levels that can be detected by standard laboratory techniques.

Despite their similarities, these assays have significant differences that influence their application in the investigation into these disorders. PMCA utilizes mammalian brain homogenates as a source of substrate and uses Western blotting as a detection system whilst RT-QuIC uses recombinant proteins as substrates and Thioflavin fluorescence to detect aggregation. RT-QuIC utilises a 96-well format that together with the fluorescent read-out makes it suitable for diagnostic applications. Whilst PMCA has been shown to reflect the biological mechanisms underlying protein misfolding, and thus is a valuable tool in understanding the pathobiology of these disorders.

This Research Topic will review the current knowledge of the application of these protein amplification tools in terms of diagnosis and understanding the biology of these disorders. Specifically, the application of these techniques in the diagnosis of CJD and other related prion disorders and their potential use in the diagnosis of PD, LBD and MSA will be addressed. The state of art in relation to the detection of other misfolding proteins such as tau proteins and their potential application in the differential diagnosis of tauopathies and the use of these assays for the detection of misfolded proteins co-occurrence will be reviewed as well as the implications for potential therapeutic interventions.
We are looking for a comprehensive and up-to-date review of the current research and/or developments in the following fields:

1. Review of the RT-QuIC and PMCA techniques.

2. PMCA/RT-QuIC and the pathobiology of human and animal disorders caused by protein misfolding:
aaaaa. Use of PMCA in animal models of prion transmission or to detect infectivity, identification of strains and sub-types CJD.
aaaab. RT-QuIC and the identification of sub-types of sporadic CJD or strains of a-synuclein in alpha-synucleinopathies.
aaaac. RT-QuIC in the diagnosis and pathobiology of animal prion diseases like chronic wasting disease or scrapie in goats and sheep.

3. Use of RT-QuIC for diagnosis of prion diseases.

4. Use of protein aggregation assays in diagnosis of a-synucleinopathies like idiopathic and genetic PD, Lewy body disease or MSA.

5. Use of RT-QuIC in tauopathies.

6.PMCA and diagnosis of variant CJD.

7. Future of protein aggregation assays like the detection of co-pathologies, the detection of other protein misfolding disorders (HD and MND/FTD) and finally the importance to therapeutic interventions.

Keywords: protein mis-folding, RT-QuIC, PMCA, Creutzfeldt-Jakob disease, Parkinson's disease, Lewy body dementia, Alzheimer's disease, prion protein, PrP, alpha-synuclein, tau protein

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